ESHG: Lipid Genes Signal Diabetes, Heart Disease

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Note that these studies were published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that these studies suggest that cardiovascular events and progression to diabetes may be associated with genetic alterations in lipid metabolism which can be identified and potentially used as predictors of risk.

The genes that control lipid levels may be an early predictor of diabetes as well as atherosclerosis and heart disease, researchers reported in two separate studies.

In one study, the lipid component dihydroceramide (dhCer) coded by a region on chromosome 3 appeared to be a diabetes risk factor independent of glucose and insulin levels, Joanne E. Curran, PhD, of the Texas Biomedical Research Institute in San Antonio, and colleagues found.

In another, a risk score pooling small effects of common genetic variants predicted carotid plaque and arterial wall thickness as well as coronary heart disease, reported Sara Willems, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues.

Both studies were presented at the European Society of Human Genetics meeting in Amsterdam.

Traditional clinical risk factors can predict diabetes and heart disease already, but adding genetic tools to the mix could be useful, particularly in determining how aggressively to approach prevention in patients considered intermediate risk by conventional measures, commented Donna Arnett, PhD, MSPH, of the University of Alabama at Birmingham School of Public Health, and a spokesperson for the American Heart Association.

The cost of genetic testing could be a hurdle for clinical application, though, until ways are found to make it more affordable, she noted in an interview with MedPage Today.

Willems' group used the population-based Rotterdam Study and the Erasmus Rucphen Family Study, a Dutch family-based cohort, to look at top lipid-associated single nucleotide polymorphisms (SNPs) identified by a recent genome-wide meta-analysis.

The studies included a total of 10,212 individuals with measurements of carotid intima media thickness (IMT) and plaques. The Rotterdam Study also included information on incident heart disease during a mean follow-up of about 11 years.

After adjustment for age and sex, the LDL cholesterol-linked genetic risk score was associated with carotid IMT (P=0.021) and even more strongly associated with plaque (P=1.7x10-8).

These relationships remained essentially unchanged with exclusion of individuals with preexisting heart disease and after adjustment for additional factors.

A risk score based on genes linked to HDL cholesterol had only a "nominally" significant link to plaque (P=0.049), while a triglyceride gene risk score wasn't associated with clinical outcomes at all.

According to Curran et al, "lipid molecules may represent endophenotypes that are closer to gene action than classical lipid markers." Following that trail, they dug deeper, looking at 356 different species of lipids in a cohort of 1,202 Mexican Americans in the San Antonio Family Heart Study.

Analysis of more than one million SNPs in quantitative and genome-wide association analyses suggested that most of the lipid species followed lines of inheritance.

Among them, 128 lipid species predicted diabetes incidence over about 10 years of follow-up. The single best predictor of progression to diabetes was dihydroceramide 18:0, which was significantly heritable (P=1.6×10-9) and markedly more common among diabetics (P=2.5×10-7).

Incident diabetes cases showed higher levels of the lipid species at baseline than those who didn't progress to diabetes (P=2.2×10-8), an association that remained significant at a P-value of 0.00012 after adjustment for baseline fasting glucose and insulin levels.

The researchers suggested dihydroceramide might be an independent predictor of risk that could be an earlier indicator than the clinical manifestations.

Two rare SNPs on chromosome 3p22 were linked to dihydroceramide levels (P=9×10-8).

"We are optimistic that our discovery will lead to new treatments, but in the short-term, the importance of finding out at an early stage whether any individual is likely to develop it cannot be overstated," Curran was quoted as saying in a press release.

"A test based on dihydroceramide levels will help to avoid the serious health effects that diabetes has in its own right, such as kidney failure, amputations, and blindness. It is, of course, also a risk for cardiovascular disease, so the health burden of this condition is enormous," she added.

But Arnett cautioned that lipodemic profiling is still in its infancy and more information is needed on how measures like dihydroceramide might measure up against clinical factors like waist circumference.

Willems' LDL data also left out mention of nongenetic factors that might have accounted for more of the variation in risk seen, she noted.

The San Antonio Family Heart Study sample recruitment and the lipid profiling was supported by the National Institutes of Health, while genome-wide genotyping was paid for by philanthropic funds.

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